Despite changes in lifestyle and new pharmacologic approaches, coronary artery diseases including myocardial infarction continue to be the principal cause of death in many countries (Breslow, J. L., Nature Med. 3, 600-601, 1997; Braunwald, E., N. Engl. J. Med., 337, 1360-1369, 1997). Accordingly, the identification of genetic and environmental factors in the onset of these diseases is highly anticipated.
Common genetic variants are known to be significantly associated with risks of contacting lifestyle-related diseases such as diabetes mellitus and hypertension (Risch, N., et al., Science, 273, 1516-1517, 1996; Collins, F. S., et al., Science, 278, 1580-1581, 1997; Lander, E. S., et al., Science, 274, 536-539, 1996). To identify genes susceptible to polygenic diseases, a method utilizing “linkage” and a method utilizing “association” are known. Linkage-based analysis involves detecting whether the locus of a gene susceptible to a disease and the locus of a gene marker (mainly microsatellite) are linked; that is, examining the relationship between gene loci. In contrast, association-based analysis involves detecting which type (allele) of specific gene markers (mainly single nucleotide polymorphisms: SNPs) is associated with a disease; that is, examining the relationship between alleles. Hence, it can be said that association-based analysis using common variants as markers is far more powerful than linkage-based analysis utilizing localization of genes related to such diseases. Single nucleotide polymorphisms (SNPs) can be useful polymorphism markers when genes associated with vulnerability to diseases or drug reactivity are searched for. SNPs may directly affect gene products quantitatively and qualitatively or may increase the risk of severe side effects due to diseases or drugs. Therefore, it is expected that the search for many SNPs can contribute to identification of disease-related genes and to the establishment of diagnostic methods whereby side effects of drugs can be avoided.
In a region of approximately 130 kb on human chromosome 6p21, there exist lymphotoxin-α (LT-α), tumor necrosis factor-α (TNF-α), LST1, 1C7, allograft inflammatory-factor-1 (AIF-1), I kappa B-like protein (IKBL), V-ATPase G-subunit like protein (ATP6G), BAT1, MICB, and p5-1. LT-α (also known as TNF-β) is one of the cytokines produced during the earliest phase of the process of angiitis and takes a homotrimeric structure wherein β sheet structures are piled up in the shape of sandwich. LT-α activates the cytokine cascade by inducing other mediators such as interleukin-1 and adhesion molecules (Ross, R., N. Engl. J. Med., 340, 115-126, 1999). Inflammatory mediators such as cytokines are known to be involved in atheroma formation and atheroma lesions so as to induce luminal thrombosis (Ross, R., N. Engl. J. Med., 340, 115-126, 1999). IKBL is located on 6p21.3 in major histocompatibility complex (MHC) class II region. It has been reported that IKBL resembles an inhibitor (IKB) family protein of a κ light chain gene in B cells. Proteins of the IKB family have action to inhibit a nuclear factor of a κ light chain gene enhancer within B cells.
For the relationship between gene mutation and myocardial infarction, a method for determining a genetic factor of myocardial infarction by analyzing polymorphisms of a human prostacyclin synthetase gene has been known (JP Patent Publication (Kokai) No. 2002-136291 A). However, the association between a gene mutation existing in the region of approximately 130 kb on the above 6p21 and myocardial infarction has not yet been reported.